Chemistry:Indole-3-carbinol

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Indole-3-carbinol[1]
Indole-3-carbinol.png
Names
Preferred IUPAC name
(1H-Indol-3-yl)methanol
Other names
Indole-3-carbinol; 3-Indolylcarbinol; 1H-Indole-3-methanol; 3-Hydroxymethylindole; 3-Indolemethanol; Indole-3-methanol; I3C
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
EC Number
  • 211-836-2
RTECS number
  • NL9483000
UNII
Properties
C9H9NO
Molar mass 147.177 g·mol−1
Appearance Off-white solid
Melting point 96 to 99 °C (205 to 210 °F; 369 to 372 K)
Partially in cold water[vague]
Hazards
GHS pictograms GHS07: Harmful
GHS Signal word warning
NFPA 704 (fire diamond)
Flammability code 0: Will not burn. E.g. waterHealth code 1: Exposure would cause irritation but only minor residual injury. E.g. turpentineReactivity code 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g. liquid nitrogenSpecial hazards (white): no codeNFPA 704 four-colored diamond
0
1
0
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references
Tracking categories (test):

Indole-3-carbinol (I3C, C9H9NO) is produced by the breakdown of the glucosinolate glucobrassicin, which can be found at relatively high levels in cruciferous vegetables such as broccoli, cabbage, cauliflower, brussels sprouts, collard greens and kale. It is also available in dietary supplements.[3] Indole-3-carbinol is the subject of on-going biomedical research into its possible anticarcinogenic,[4] antioxidant, and anti-atherogenic effects.[5] Research on indole-3-carbinol has been conducted primarily using laboratory animals and cultured cells.[6] Limited and inconclusive human studies have been reported. A recent review of the biomedical research literature found that "evidence of an inverse association between cruciferous vegetable intake and breast or prostate cancer in humans is limited and inconsistent" and "larger randomized controlled trials are needed" to determine if supplemental indole-3-carbinol has health benefits.[7]

Indole-3-carbinol and cancer

Investigation of mechanisms by which consumption of indole-3-carbinol might influence cancer incidence focuses on its ability to alter estrogen metabolism and other cellular effects. Controlled studies have been performed on such animals as rats, mice, and rainbow trout, introducing various controlled levels of carcinogens, and levels of indole-3-carbinol into their daily diet. Results showed dose-related decreases in tumor susceptibility due to indole-3-carbinol (inferred by decreases in aflatoxin–DNA binding). The first direct evidence of pure anti-initiating activity by a natural anticarcinogen (indole-3-carbinol) found in human diet was claimed by Dashwood et al. in 1989.[8]

Indole-3-carbinol induces a G1 growth arrest of human reproductive cancer cells.[9] This is potentially relevant to the prevention and treatment of cancer, as the G1 phase of cell growth occurs early in the cell life cycle, and, for most cells, is the major period of cell cycle during its lifespan. The G1 phase is marked by synthesis of various enzymes that are required in the next ("S") phase, including those needed for DNA replication.

Overuse of indole-3-carbinol supplements in the hope of preventing cancer may be unwise, as the hormone balance should be tested (via simple blood test) before regular consumption. Such caution is advised, due to its effect on estrogen levels (estrogen has a significant impact on brain function).[10][11]

It promotes liver cancer in trout when it is combined with aflatoxin B1 and demotes metastasis.[6]

Melanoma

Indole-3-carbinol causes proliferation arrest and apoptosis in human melanoma cells. Kim et al. (2011) showed that the master regulator of melanoma biology, microphthalmia-associated transcription factor (MITF-M) was downregulated by indole-3-carbinol to induce apoptosis.[12] Kundu et al. (2017) demonstrated that the anticancer property of indole-3-carbinol is driven by specific targeting of oncogenic pathways.[13][14] In two different studies using xenografted mouse model of melanoma, they observed that subcutaneous injection of indole-3-carbinol could bring down tumor burden significantly. The underlying molecular mechanism of this anti-tumor effect was found to be by the specific inhibition of activity of oncogenic BRAFV600E in tumors that harbored the mutation. However, in tumors that expressed wild type BRAF, indole-3-carbinol did not cause any comparable antiproliferative effect. Additionally indole-3-carbinol did not cause antiproliferation even in normal epidermal melanocytes underscoring the specificity and selectivity of its action. Kundu et al.[citation needed] further showed that inhibition of BRAF V600E activity by indole-3-carbinol resulted in downregulation of MITF-M by downstream signaling which caused a G1 cell cycle arrest leading to the observed antiproliferative effect.

In a second study Kundu et al.[citation needed] showed that in melanoma cells where PTEN is downregulated, indole-3-carbinol directly interacts with NEDD41 to prevent PTEN ubiquitination and subsequent proteasomal degradation. This results in stabilization of PTEN and inhibition of proliferation by downstream AKT signaling. Overall scientific evidence shows that in melanoma, indole-3-carbinol specifically inhibits the two most commonly associated driver mutation signaling pathways to cause proliferation, a fact that can be used to design clinical trial to treat human patients with indole-3-carbinol in future.

Systemic lupus erythematosus

Indole-3-carbinol can shift estrogen metabolism towards less estrogenic metabolites. Systemic lupus erythematosus (SLE, or lupus), an autoimmune disease, is associated with estrogen. In a study using mice bred to develop lupus, indole-3-carbinol was fed to one group while another group was fed a standard mouse diet; the group fed the indole-3-carbinol diet lived longer and had fewer signs of disease.[15]

Another study of lupus-prone mice with indole-3-carbinol defined the mechanism for the improvement of their disease to be due to sequential blocks in the development of B and T cells of these mice. The maturation arrests resulted in a fall in autoantibody production, thought to be a crucial component of lupus causation. In addition, I3C supplementation of the disease prone mice led to a normalization of their T cell function.[16]

Women with lupus can manifest a metabolic response to indole-3-carbinol and might also benefit from its antiestrogenic effects. Clinical trials are currently underway to determine the efficacy of treating human patients with lupus using indole-3-carbinol.

Effect in recurrent respiratory papillomatosis

There is evidence suggesting that indole-3-carbinol may have an effect on human papillomavirus-infected cells in both pediatrics and adult patients.[17][18] Research is ongoing.

References

  1. ↑ Data at chemblink.com
  2. ↑ GHS: Sigma-Aldrich i7256
  3. ↑ Sarubin-Fragakis, A.; Thomson, C.; American Dietetic Association (2007) (in en). The Health Professional's Guide to Popular Dietary Supplements. American Dietetic Association. p. 312. ISBN 9780880913638. https://books.google.com/books?id=KA8vU6XKfIAC. 
  4. ↑ Park, N. I.; Kim, J. K.; Park, W. T.; Cho, J. W.; Lim, Y. P.; Park, S. U. (2010). "An efficient protocol for genetic transformation of watercress (Nasturtium officinale) using Agrobacterium rhizogenes". Molecular Biology Reports 38 (8): 4947–4953. doi:10.1007/s11033-010-0638-5. PMID 21161399. 
  5. ↑ "indole-3-methanol (CHEBI:24814)". Chemical Entities of Biological Interest (ChEBI). European Bioinformatics Institute. https://www.ebi.ac.uk/chebi/searchId.do;jsessionid=730287C45988EA839FB9B53AC7E0A6CA?chebiId=CHEBI:24814. 
  6. ↑ 6.0 6.1 Tilton, S. C.; Hendricks, J. D.; Orner, G. A.; Pereira, C. B.; Bailey, G. S.; Williams, D. E. (2007). "Gene expression analysis during tumor enhancement by the dietary phytochemical, 3,3′-diindolylmethane, in rainbow trout". Carcinogenesis 28 (7): 1589–1598. doi:10.1093/carcin/bgm017. PMID 17272308. 
  7. ↑ Higdon, J.; Delage, B.; Williams, D.; Dashwood, R. (2007). "Cruciferous vegetables and human cancer risk: Epidemiologic evidence and mechanistic basis". Pharmacological Research 55 (3): 224–236. doi:10.1016/j.phrs.2007.01.009. PMID 17317210. 
  8. ↑ Dashwood, R. H.; Arbogast, D. N.; Fong, A. T.; Pereira, C.; Hendricks, J. D.; Bailey, G. S. (1989). "Quantitative inter-relationships between aflatoxin B1 carcinogen dose, indole-3-carbinol anti-carcinogen dose, target organ DNA adduction and final tumor response". Carcinogenesis 10 (1): 175–181. doi:10.1093/carcin/10.1.175. PMID 2491968. 
  9. ↑ Hsu, J.; Dev, A.; Wing, A.; Brew, C.; Bjeldanes, L.; Firestone, G. (2006). "Indole-3-carbinol mediated cell cycle arrest of LNCaP human prostate cancer cells requires the induced production of activated p53 tumor suppressor protein". Biochemical Pharmacology 72 (12): 1714–1723. doi:10.1016/j.bcp.2006.08.012. PMID 16970927. 
  10. ↑ Culmsee, C.; Vedder, H.; Ravati, A.; Junker, V.; Otto, D.; Ahlemeyer, B.; Krieg, J.-C.; Krieglstein, J. (1999). "Neuroprotection by Estrogens in a Mouse Model of Focal Cerebral Ischemia and in Cultured Neurons: Evidence for a Receptor-Independent Antioxidative Mechanism". Journal of Cerebral Blood Flow & Metabolism 19 (11): 1263–1269. doi:10.1097/00004647-199911000-00011. PMID 10566973. 
  11. ↑ "Estrogen's Influence on the Brain". Society for Neuroscience. http://www.sfn.org/index.cfm?pagename=brainBriefings_estrogensInfluenceOnTheBrain. 
  12. ↑ Kim, S.-Y.; Kim, D.-S.; Jeong, Y.-M.; Moon, S.-I.; Kwon, S.-B.; Park, K.-C. (2011). "Indole-3-carbinol and ultraviolet B induce apoptosis of human melanoma cells via down-regulation of MITF". Pharmazie 66 (12): 982–987. PMID 22312706. 
  13. ↑ Kundu, A.; Quirit, J. G.; Khouri, M. G.; Firestone, G. L. (2017). "Inhibition of oncogenic BRAF activity by indole-3-carbinol disrupts microphthalmia-associated transcription factor expression and arrests melanoma cell proliferation". Molecular Carcinogenesis 56 (1): 49–61. doi:10.1002/mc.22472. PMID 26878440. 
  14. ↑ Kundu, A.; Aronchik, I.; Quirit, J. G.; Firestone, G. L. (2014). "The antiproliferative response of indole-3-carbinol in human melanoma cells is triggered by an interaction with NEDD4-1 and disruption of wild-type PTEN degradation". Molecular Cancer Research 12 (11): 1621–1634. doi:10.1158/1541-7786.MCR-14-0018. PMID 25009292. 
  15. ↑ Auborn, K. J.; Qi, M.; Yan, X.-J.; Teichberg, S.; Chen, D.; Madaio, M. P.; Chiorazzi, N. (2003). "Lifespan is prolonged in autoimmune-prone (NZB/NZW) F1 mice fed a diet supplemented with indole-3-carbinol". The Journal of Nutrition 133 (11): 3610–3613. doi:10.1093/jn/133.11.3610. PMID 14608082. 
  16. ↑ Yan, X.-J.; Qi, M.; Telusma, G.; Yancopoulos, S.; Madaio, M.; Satoh, M.; Reeves, W. H.; Teichberg, S. et al. (2009). "Indole-3-carbinol improves survival in lupus-prone mice by inducing tandem B- and T-cell differentiation blockades". Clinical Immunology 131 (3): 481–494. doi:10.1016/j.clim.2009.01.013. PMID 19278904. 
  17. ↑ Rosen, C. A.; Bryson, P. C. (2004). "Indole-3-Carbinol for recurrent respiratory papillomatosis: Long-term results". Journal of Voice 18 (2): 248–253. doi:10.1016/j.jvoice.2003.05.005. PMID 15193659. 
  18. ↑ Rosen, C. A.; Woodson, G. E.; Thompson, J. W.; Hengesteg, A. P.; Bradlow, H. L. (1998). "Preliminary results of the use of indole-3-carbinol for recurrent respiratory papillomatosis". Otolaryngology–Head and Neck Surgery 118 (6): 810–815. doi:10.1016/S0194-5998(98)70274-8. PMID 9627242. 

Further reading

  • Michnovicz, J. J.; Bradlow, H. L. (1990). "Induction of Estradiol Metabolism by Dietary Indole-3-carbinol in Humans". Journal of the National Cancer Institute 82 (11): 947–949. doi:10.1093/jnci/82.11.947. PMID 2342128. 
  • Morgan, David Owen (2007). The Cell Cycle: Principles of Control. London: New Science Press. ISBN 978-0-87893-508-6. 

External links



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